TY - JOUR
T1 - Structural basis of THC analog activity at the Cannabinoid 1 receptor
AU - Thorsen, Thor S.
AU - Kulkarni, Yashraj
AU - Sykes, David A.
AU - Bøggild, Andreas
AU - Drace, Taner
AU - Hompluem, Pattarin
AU - Iliopoulos-Tsoutsouvas, Christos
AU - Nikas, Spyros P.
AU - Daver, Henrik
AU - Makriyannis, Alexandros
AU - Nissen, Poul
AU - Gajhede, Michael
AU - Veprintsev, Dmitry B.
AU - Boesen, Thomas
AU - Kastrup, Jette S.
AU - Gloriam, David E.
N1 - Publisher Copyright:
© 2025. The Author(s).
PY - 2025
Y1 - 2025
N2 - Tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC's psychoactive actions are mediated primarily by the cannabinoid receptor CB1. Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB1 and its primary transducer, Gi1. We leverage this structure for docking and 1000 ns molecular dynamics simulations of THC and 10 structural analogs delineating their spatiotemporal interactions at the molecular level. Furthermore, we pharmacologically profile their recruitment of Gi and β-arrestins and reversibility of binding from an active complex. By combining detailed CB1 structural information with molecular models and signaling data we uncover the differential spatiotemporal interactions these ligands make to receptors governing potency, efficacy, bias and kinetics. This may help explain the actions of abused substances, advance fundamental receptor activation studies and design better medicines.
AB - Tetrahydrocannabinol (THC) is the principal psychoactive compound derived from the cannabis plant Cannabis sativa and approved for emetic conditions, appetite stimulation and sleep apnea relief. THC's psychoactive actions are mediated primarily by the cannabinoid receptor CB1. Here, we determine the cryo-EM structure of HU210, a THC analog and widely used tool compound, bound to CB1 and its primary transducer, Gi1. We leverage this structure for docking and 1000 ns molecular dynamics simulations of THC and 10 structural analogs delineating their spatiotemporal interactions at the molecular level. Furthermore, we pharmacologically profile their recruitment of Gi and β-arrestins and reversibility of binding from an active complex. By combining detailed CB1 structural information with molecular models and signaling data we uncover the differential spatiotemporal interactions these ligands make to receptors governing potency, efficacy, bias and kinetics. This may help explain the actions of abused substances, advance fundamental receptor activation studies and design better medicines.
U2 - 10.1038/s41467-024-55808-4
DO - 10.1038/s41467-024-55808-4
M3 - Journal article
C2 - 39779700
AN - SCOPUS:85215130189
VL - 16
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 486
ER -